1. Field of the Invention
The invention relates to a method for producing microparticles or nanoparticles of water-soluble and water-insoluble substances by controlled precipitation, co-precipitation and self-organization processes in microjet reactors, a solvent, which contains at least one target molecule, and a nonsolvent being mixed as jets that collide with each other in a microjet reactor at defined pressures and flow rates to effect very rapid precipitation, co-precipitation or a chemical reaction, during the course of which microparticles or nanoparticles are formed.
The invention relates further to a device for producing microparticles or nanoparticles of water-soluble and water-insoluble substances in microjet reactors, said device having at least two nozzles each of which has its own pump and feed line for injecting one liquid medium in each case into a reactor chamber enclosed in a reactor housing and on to a shared collison point, the reactor housing being provided with a first opening through which a gas can be introduced so as to maintain the gaseous atmosphere within the reactor, notably at the collision point of the two liquid jets, and to cool the resulting products, and a further opening for removing the resulting products and excess gas out of the reactor housing.
2. Description of the Related Art
In numerous branches of industry, in particular in the medical and pharmaceutical fields, there is a frequent need to micronize or nanosize large particles. These methods are being used increasingly often, particularly in the pharmaceutical field, to enhance the bioavailability of active ingredients or to deliver one or more active ingredients to a targeted site of action.
The term bioavailability refers to the degree to which an active ingredient, following administration thereof, can be made available to the targeted tissue. Many factors are known to influence bioavailability, for example, a substance's solubility in water, it's release rate or particle size. Micronizing or nanosizing substances that dissolve poorly in water thus enhances their bioavailability, either by improving their solubility or increasing their release rate.
Another method of enhancing bioavailability is via drug targeting or drug delivery, whereby particles are distributed in the target tissue according to their size or are engineered such as to have suitable surface modifications enabling them to reach the targeted site of absorption or action.
Such methods of producing microparticles and nanoparticles are described in various patent applications and patents, for example in U.S. Pat. Nos. 5,833,891 A, 5,534,270 A, 6,862,890 B, 6,177,103 B, DE 10 2005 053 862 A1, U.S. Pat. Nos. 5,833,891 A, 5,534,270 A, 6,862,890 B, 6,177,103 B, DE 10 2005 017 777 A1 and DE 10 2005 053 862 A1.
WO 02/60275 A1 describes methods of producing nanoparticles in which two immiscible liquids are charged electrically so as to achieve encapsulation. In this case, the use of toxic substances is not ruled out, meaning that product quality may suffer considerably as a result. Particle size, moreover, cannot be controlled with this method.
US 2009/0214655 A1 also describes the use of two immiscible liquids. Although a microreactor is used there to produce the nanoparticles, only the production of emulsions is described. In addition, the nanoparticles are produced in a liquid-filled space in which, once again, it is impossible to control either particle size or the particle properties. Furthermore, the device can easily become blocked due to the fact that the reactions are carried out in microchannels.
The known techniques for producing nanoparticles have many disadvantages.
“Top-down” techniques, most of which involve mechanical crushing processes such as dry or wet milling, run the risk of microbial contamination, contamination from milling-ball abrasion or degradation of the active ingredient, particularly since very lengthy milling times are needed to micronize the active ingredient. In the case of dry milling, moreover, the smallest obtainable particle size even after very lengthy milling times is still approx. 100 micrometers.
A number of “bottom-up” approaches exist for the production of nanoparticles, such as salting out, emulsification, solvent evaporation or spray vaporisation of supercritical liquids.
No matter which of these approaches is used to produce pharmaceutical nanoparticles, an increase in surface area will always be obtained compared to that of particles exceeding 1 μm in size.
The increase in surface area and in surface interactions may positively influence the release rate and make it possible to control the pharmacokinetic properties of a drug. Most of these methods, nevertheless, have the following limitations: high energy input; low level of success; upscaling problems (transition from laboratory experiment to industrial-scale production); particle size and properties are difficult to control; relatively toxic organic solvents have to be used or the methods themselves are difficult to carry out. These factors limit the use of these methods for the commercial production of nanoparticles.
As one of the various methods mentioned, the nano-precipitation or solvent-exchange method was described in U.S. Pat. No. 5,118,529 A. This relatively simple method includes the formation of nanoparticles by means of solvent/nonsolvent precipitation in a single step. Ideally, the polymer and the active ingredient are dissolved in the same solvent so as to be precipitated as nanoparticles on contact with the nonsolvent (usually water).
The rapid formation of nanoparticles is caused by the Marangoni effect as a result of eddies at the solvent/nonsolvent collision point and of diffusion of solvent into the nonsolvent.
Precipitation results in the production of nanoparticles measuring 100 to 300 nm and showing relatively narrow particle distribution when various polymers are used. Surface modifiers are not required in all cases. Normally, use is made only of non-toxic solvents.
The described prior art discloses that, especially in the pharmaceutical industry, novel methods are needed that avoid all the disadvantages connected with the conventional methods outlined above.
DE 10 2009 008 478 A1 describes a method in which solvent/anti-solvent precipitation with in-situ spray drying occurs in the presence of surface-active molecules, wherein a microjet reactor of the kind described in EP 1 165 224 B1 is used. A microjet reactor of this kind has at least two nozzles each of which has its own pump and feed line for injecting one liquid medium in each case into a reactor chamber enclosed in a reactor housing and on to a shared collision point, the reactor housing being provided with a first opening through which a gas, an evaporating liquid, a cooling liquid or a cooling gas can be introduced so as to maintain the gaseous atmosphere within the reactor, notably at the collision point of the two liquid jets, and to cool the resulting products, and a further opening for removing the resulting products and excess gas out of the reactor housing. Accordingly, a gas, an evaporating liquid or a cooling gas is introduced via an opening into the reactor chamber so as to maintain a gaseous atmosphere within the reactor, notably at the collision point of the two liquid jets, and to cool the resulting products, and the resulting products together with excess gas are removed from the reactor housing through an opening by positive pressure on the gas input side or negative pressure on the product and gas discharge side.
In DE 10 2009 008 478 A1, the active ingredient and a surface-active molecule are dissolved in a water-miscible organic phase. This organic solution and water, which serves as nonsolvent, are pumped, each through a dedicated stainless steel capillary and at a constant flow rate and pressure, by two pumps into the microreactor (referred to as the “microjet reactor”), where they collide as impinging jets. Within the reactor, solvent and nonsolvent are mixed very rapidly, the active ingredient precipitating out as nanoparticles and the resulting nanoparticle suspension being expelled from the microjet reactor either by very hot compressed air or an inert gas.
The gas vaporizes the organic solvent and the water to the effect that, after both liquid phases have vaporized, the nanoparticles of active ingredient are coated with the surface-modifying molecules. At the end of the process the nanoparticles are in powder-form.
The essential element in DE 10 2009 008 478 A1 is thus the use of heated air or an inert gas, together with a surface modifier, in such a manner that the solvent and the nonsolvent vaporize as the active ingredient precipitates and the surface modifiers coat the nanoparticles, thereby preventing further aggregation of the particles and Ostwald growth.
Although particle size can be efficiently controlled with the method described in DE 10 2009 008 478 A1, the necessity of using surface modifiers constitutes a constraint on the use of this technology for diverse microparticle or nanoparticle production strategies.